tbuckley/cabot-search huggingface dataset:
A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in <i>IDH1</i>-Mutated Myeloid Malignancies
Authors: Curtis A. Lachowiez, Sanam Loghavi, Zhihong Zeng, Tomoyuki Tanaka, Yi June Kim, Hidetaka Uryu, Sven Turkalj, Niels Asger Jakobsen, Marlise R. Luskin, Dzifa Y. Duose, Rebecca S.S. Tidwell, Nicholas J. Short, Gautam Borthakur, Tapan M. Kadia, Lucia Masarova, George D. Tippett, Prithviraj Bose, Elias J. Jabbour, Farhad Ravandi, Naval G. Daver, Guillermo Garcia-Manero, Hagop Kantarjian, Jacqueline S. Garcia, Paresh Vyas, Koichi Takahashi, Marina Konopleva, Courtney D. DiNardo
Journal: Blood Cancer Discovery (2023)

The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n = 31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO + VEN + AZA versus IVO + VEN was 90% versus 83%. Among measurable residual disease (MRD)-evaluable patients (N = 16), 63% attained MRD--negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N = 14). Median event-free survival and overall survival were 36 [94% CI, 23-not reached (NR)] and 42 (95% CI, 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.
Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment
Authors: Paolo Coghi, Jinxin Li, Narayan S. Hosmane, Yinghuai Zhu
Journal: Medicinal Research Reviews (2023)

Abstract Boron neutron capture therapy (BNCT) is one of the most promising treatments among neutron capture therapies due to its long‐term clinical application and unequivocally obtained success during clinical trials. Boron drug and neutron play an equivalent crucial role in BNCT. Nevertheless, current clinically used l ‐boronophenylalanine (BPA) and sodium borocaptate (BSH) suffer from large uptake dose and low blood to tumor selectivity, and that initiated overwhelm screening of next generation of BNCT agents. Various boron agents, such as small molecules and macro/nano‐vehicles, have been explored with better success. In this featured article, different types of agents are rationally analyzed and compared, and the feasible targets are shared to present a perspective view for the future of BNCT in cancer treatment. This review aims at summarizing the current knowledge of a variety of boron compounds, reported recently, for the application of BCNT.
Dialysis on the Mind: The Evolution of Hemodialysis-Related Acute Brain Injury
Authors: Dearbhla M. Kelly
Journal: Journal of the American Society of Nephrology (2023)

1Department of Intensive Care Medicine, Mater Misericordiae University Hospital, Dublin, Ireland 2Global Brain Health Institute, Trinity College Dublin, Ireland Correspondence: Dr. Dearbhla M. Kelly, Department of Intensive Care Medicine, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, D07 R2WY, Ireland. Email: [email protected] Published online ahead of print. Publication date available at www.jasn.org. See related article, "Hemodialysis-Related Acute Brain Injury Demonstrated by Application of Intradialytic Magnetic Resonance Imaging and Spectroscopy," on pages 1090–1104.
Assessing the Influence of Climate on the Spatial Pattern of West Nile Virus Incidence in the United States
Authors: Morgan E. Gorris, James T. Randerson, Shane R. Coffield, Kathleen K. Treseder, Charles S. Zender, Chonggang Xu, Carrie A. Manore
Journal: Environmental Health Perspectives (2023)

West Nile virus (WNV) is the leading cause of mosquito-borne disease in humans in the United States. Since the introduction of the disease in 1999, incidence levels have stabilized in many regions, allowing for analysis of climate conditions that shape the spatial structure of disease incidence.
Chi3l1 Is a Modulator of Glioma Stem Cell States and a Therapeutic Target in Glioblastoma
Authors: Charlotte Guetta-Terrier, David Karambizi, Bedia Akosman, John P. Zepecki, Jia-Shu Chen, Suchitra Kamle, J. Eduardo Fajardo, Andras Fiser, Ritambhara Singh, Steven A. Toms, Chun Geun Lee, Jack A. Elias, Nikos Tapinos
Journal: Cancer Research (2023)

Chitinase 3-like 1 (Chi3l1) is a secreted protein that is highly expressed in glioblastoma. Here, we show that Chi3l1 alters the state of glioma stem cells (GSC) to support tumor growth. Exposure of patient-derived GSCs to Chi3l1 reduced the frequency of CD133+SOX2+ cells and increased the CD44+Chi3l1+ cells. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of β-catenin, Akt, and STAT3. Single-cell RNA sequencing and RNA velocity following incubation of GSCs with Chi3l1 showed significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq revealed that Chi3l1 increases accessibility of promoters containing a Myc-associated zinc finger protein (MAZ) transcription factor footprint. Inhibition of MAZ downregulated a set of genes with high expression in cellular clusters that exhibit significant cell state transitions after treatment with Chi3l1, and MAZ deficiency rescued the Chi3L-induced increase of GSC self-renewal. Finally, targeting Chi3l1 in vivo with a blocking antibody inhibited tumor growth and increased the probability of survival. Overall, this work suggests that Chi3l1 interacts with CD44 on the surface of GSCs to induce Akt/β-catenin signaling and MAZ transcriptional activity, which in turn upregulates CD44 expression in a pro-mesenchymal feed-forward loop. The role of Chi3l1 in regulating cellular plasticity confers a targetable vulnerability to glioblastoma. Chi3l1 is a modulator of glioma stem cell states that can be targeted to promote differentiation and suppress growth of glioblastoma.
Class A capsid assembly modulator RG7907 clears HBV-infected hepatocytes through core-dependent hepatocyte death and proliferation
Authors: Dieudonné Buh Kum, Hannah Vanrusselt, Abel Acosta Sanchez, Valerio Taverniti, Eloi R. Verrier, Thomas F. Baumert, Cheng Liu, Jerome Deval, Nikky Corthout, Sebastian Munck, Leonid Beigelman, Lawrence M. Blatt, Julian A. Symons, Pierre Raboisson, Andreas Jekle, Sandrine Vendeville, Yannick Debing
Journal: Hepatology (2023)

Background and Aims: Effective therapies leading to a functional cure for chronic hepatitis B are still lacking. Class A capsid assembly modulators (CAM-As) are an attractive modality to address this unmet medical need. CAM-As induce aggregation of the HBV core protein (HBc) and lead to sustained HBsAg reductions in a chronic hepatitis B mouse model. Here, we investigate the underlying mechanism of action for CAM-A compound RG7907. Approach and Results: RG7907 induced extensive HBc aggregation in vitro , in hepatoma cells, and in primary hepatocytes. In the adeno-associated virus (AAV)–HBV mouse model, the RG7907 treatment led to a pronounced reduction in serum HBsAg and HBeAg, concomitant with clearance of HBsAg, HBc, and AAV-HBV episome from the liver. Transient increases in alanine transaminase, hepatocyte apoptosis, and proliferation markers were observed. These processes were confirmed by RNA sequencing, which also uncovered a role for interferon alpha and gamma signaling, including the interferon-stimulated gene 15 (ISG15) pathway. Finally, the in vitro observation of CAM-A–induced HBc–dependent cell death through apoptosis established the link of HBc aggregation to in vivo loss of infected hepatocytes. Conclusions: Our study unravels a previously unknown mechanism of action for CAM-As such as RG7907 in which HBc aggregation induces cell death, resulting in hepatocyte proliferation and loss of covalently closed circular DNA or its equivalent, possibly assisted by an induced innate immune response. This represents a promising approach to attain a functional cure for chronic hepatitis B.
Bioengineered exosomal-membrane-camouflaged abiotic nanocarriers: neurodegenerative diseases, tissue engineering and regenerative medicine
Authors: Daniela Lopes, Joana Lopes, Miguel Pereira-Silva, Diana Peixoto, Navid Rabiee, Francisco Veiga, Omid Moradi, Zhan-Hu Guo, Xiang-Dong Wang, João Conde, Pooyan Makvandi, Ana Cláudia Paiva-Santos
Journal: Military Medical Research (2023)

Abstract A bio-inspired strategy has recently been developed for camouflaging nanocarriers with biomembranes, such as natural cell membranes or subcellular structure-derived membranes. This strategy endows cloaked nanomaterials with improved interfacial properties, superior cell targeting, immune evasion potential, and prolonged duration of systemic circulation. Here, we summarize recent advances in the production and application of exosomal membrane-coated nanomaterials. The structure, properties, and manner in which exosomes communicate with cells are first reviewed. This is followed by a discussion of the types of exosomes and their fabrication methods. We then discuss the applications of biomimetic exosomes and membrane-cloaked nanocarriers in tissue engineering, regenerative medicine, imaging, and the treatment of neurodegenerative diseases. Finally, we appraise the current challenges associated with the clinical translation of biomimetic exosomal membrane-surface-engineered nanovehicles and evaluate the future of this technology.
Sex differences in the generalizability of randomized clinical trials in heart failure with reduced ejection fraction
Authors: Megan Schroeder, Yvonne Mei Fong Lim, Gianluigi Savarese, Kiliana Suzart‐Woischnik, Claire Baudier, Tomasz Dyszynski, Ilonca Vaartjes, Marinus J.C. Eijkemans, Alicia Uijl, Ronald Herrera, Eleni Vradi, Jasper J. Brugts, Hans‐Peter Brunner‐La Rocca, Vanessa Blanc‐Guillemaud, Sandra Waechter, Fabrice Couvelard, Benoit Tyl, Samuel Fatoba, Arno W. Hoes, Lars H. Lund, Christoph Gerlinger, Folkert W. Asselbergs, Diederick E. Grobbee, Maureen Cronin, Stefan Koudstaal
Journal: European Journal of Heart Failure (2023)

Aims In order to understand how sex differences impact the generalizability of randomized clinical trials (RCTs) in patients with heart failure (HF) and reduced ejection fraction (HFrEF), we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex. Methods and results Data from two HF registries and five HFrEF RCTs were used to create three subpopulations: one RCT population ( n = 16 917; 21.7% females), registry patients eligible for RCT inclusion ( n = 26 104; 31.8% females), and registry patients ineligible for RCT inclusion ( n = 20 810; 30.2% females). Clinical endpoints included all‐cause mortality, cardiovascular mortality, and first HF hospitalization at 1 year. Males and females were equally eligible for trial enrolment (56.9% of females and 55.1% of males in the registries). One‐year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT‐eligible, and RCT‐ineligible groups, respectively. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT‐eligible females (standardized mortality ratio [SMR] 0.72; 95% confidence interval [CI] 0.62–0.83), while RCT males showed higher adjusted mortality rates compared to RCT‐eligible males (SMR 1.16; 95% CI 1.09–1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95% CI 0.76–1.03 for females, SMR 1.43; 95% CI 1.33–1.53 for males). Conclusion Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and female trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries.
Unprecedented Outbreak of West Nile Virus — Maricopa County, Arizona, 2021
Authors: Melissa Kretschmer, Irene Ruberto, John Townsend, Karen Zabel, James Will, Keila Maldonado, Nicole Busser, Dan Damian, Ariella P. Dale
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

West Nile virus (WNV) is a mosquitoborne disease primarily transmitted through bites of infected Culex species mosquitos (1). In the United States, WNV is the leading domestically acquired arboviral disease; it can cause severe illness affecting the brain and spinal cord with an associated case fatality rate of 10% (2,3). On September 2, 2021, Maricopa County Environmental Services Department, Vector Control Division (MCESD-VCD) notified the Maricopa County Department of Public Health (MCDPH) and the Arizona Department of Health Services (ADHS) that the WNV vector index (VI), a measure of infected Culex mosquitoes, was substantially elevated. By that date, at least 100 WNV cases had already been reported among Maricopa County residents to MCDPH by health care providers and laboratories. Within 2 weeks, the VI reached its highest ever recorded level (53.61), with an associated tenfold increase in the number of human disease cases. During 2021, a total of 1,487 human WNV cases were identified; 956 (64.3%) patients had neuroinvasive disease, and 101 (6.8%) died. MCESD-VCD conducted daily remediation efforts to mitigate elevated VI and address mosquito-related complaints from residents (i.e., large numbers of outdoor mosquitoes from an unknown source and unmaintained swimming pools potentially breeding mosquitoes). MCDPH increased outreach to the community and providers through messaging, education events, and media. This was the largest documented focal WNV outbreak in a single county in the United States (4). Despite outreach efforts to communities and health care partners, clinicians and patients reported a lack of awareness of the WNV outbreak, highlighting the need for public health agencies to increase prevention messaging to broaden public awareness and to ensure that health care providers are aware of recommended testing methods for clinically compatible illnesses.
Association of SARS-CoV-2 Antibody Level With Risk of Infection or Hospitalization—Reply
Authors: Thomas Starkey, Michael Tilby, Lennard Y. W. Lee
Journal: JAMA Oncology (2023)

In Reply We thank Long et al for commenting on our national COVID-19 cancer evaluation. 1 To our knowledge, this was the first study to show that the absence of immune or antibody responses was observed frequently in patients with cancer, and this absence was associated with increased SARS-CoV-2 infection risk.First, Long et al suggest we performed a retrospective study.This is a misinterpretation, as there was no "jumping backward."Our research program encompasses 86 cancer centers, with 250 people contributing since 2020. 2 Our team provided antibody response evaluation for the period of September 1, 2021, to March 4, 2022, and monitored each patient for outcomes. 1Our evaluation was therefore a cross-sectional observational study. 3or the second point, Long et al suggest that "systemic anticancer therapies should be included in the multivariate analysis."Our models were adjusted for age, sex, ethnicity, and deprivation levels.This approach enables comparisons with other studies of SARS-CoV-2 vaccine effectiveness. 4,5We accept that further iterations and evolution of the multivariable models can always be performed.In the future, with larger cohorts, the risk of overfitting might be mitigated by including new parameters, such as the type of SARS-CoV-2 variant, and highly granular analyses of the different types of systemic anticancer therapies.However, we believe that the pursuit of better models and ever larger studies should not detract from key findings that patients with cancer more frequently had absent immune or antibody responses and that this was associated with significantly elevated risk.Lastly, the authors propose that "antibody levels should be compared between patients with tumors and the general population at the same time interval."As noted, we were indeed the first pandemic consortium to identify waning effectiveness in patients with cancer.This point was mentioned in the Limitations section. 1 The challenge to the field is that patients with cancer may now be on their first or seventh cancer vaccine booster, with various formulation(s) (eg, messenger RNA or adenoviral vector) administered at relatively different time intervals.This is the nature of real-world data when assessing real-world patients outside of the original licensing vaccine trials from which they were excluded from partaking.We have tried to ensure that we do not mislead the reader by making assumptions with regard to associations between SARS-CoV-2 antibody responses and differences in SARS-CoV-2 vaccination time intervals, and not accurately evaluating the bigger picture.
Characteristics of Esketamine Prescribers Among Medicare Beneficiaries in the United States, 2019-2020
Authors: John L. Havlik, Michael J. Murphy, Nina Gong, Deanna Tang, John H. Krystal
Journal: JAMA Network Open (2023)

This cross-sectional study examines the characteristics and geographic distribution of eskatamine prescribers among Medicare beneficiaries in the US from 2019 to 2020.
Eosinophils from A to Z
Authors: Lea Gigon, Timothée Fettrelet, Shida Yousefi, Dagmar Simon, Hans‐Uwe Simon
Journal: Allergy (2023)

Abstract Eosinophils are bone marrow‐derived granulocytes and are found in low numbers in the peripheral blood of healthy subjects. In type 2 inflammatory diseases, eosinopoiesis in the bone marrow is increased, resulting in a rise in the number of mature eosinophils released in the circulation. From the blood, eosinophils can migrate in multiple tissues and organs under both physiological and pathological conditions. Eosinophils exert their various functions through the synthesis and release of a variety of granule proteins and pro‐inflammatory mediators. Despite being present in all species of vertebrates, the functional role of eosinophils is still a matter of debate. Eosinophils may play a role in host defense against various pathogens. In addition, eosinophils have been reported to be involved in tissue homeostasis and exhibit immunomodulatory activities. In this review, we aim to provide a broad overview of eosinophil biology and eosinophilic diseases in a lexicon‐style format using keywords starting from A until Z with cross‐references to other chapters indicated in italics in the text or specified in parentheses.
Home working and social and mental wellbeing at different stages of the COVID-19 pandemic in the UK: Evidence from 7 longitudinal population surveys
Authors: Jacques Wels, Bożena Wielgoszewska, Bettina Moltrecht, Charlotte Booth, Michael J. Green, Olivia KL Hamilton, Evangelia Demou, Giorgio Di Gessa, Charlotte Huggins, Jingmin Zhu, Gillian Santorelli, Richard J. Silverwood, Daniel Kopasker, Richard J. Shaw, Alun Hughes, Praveetha Patalay, Claire Steves, Nishi Chaturvedi, David J. Porteous, Rebecca Rhead, Srinivasa Vittal Katikireddi, George B. Ploubidis
Journal: PLoS Medicine (2023)

Background Home working has increased since the Coronavirus Disease 2019 (COVID-19) pandemic’s onset with concerns that it may have adverse health implications. We assessed the association between home working and social and mental wellbeing among the employed population aged 16 to 66 through harmonised analyses of 7 UK longitudinal studies. Methods and findings We estimated associations between home working and measures of psychological distress, low life satisfaction, poor self-rated health, low social contact, and loneliness across 3 different stages of the pandemic (T1 = April to June 2020 –first lockdown, T2 = July to October 2020 –eased restrictions, T3 = November 2020 to March 2021 –second lockdown) using modified Poisson regression and meta-analyses to pool results across studies. We successively adjusted the model for sociodemographic characteristics (e.g., age, sex), job characteristics (e.g., sector of activity, pre-pandemic home working propensities), and pre-pandemic health. Among respectively 10,367, 11,585, and 12,179 participants at T1, T2, and T3, we found higher rates of home working at T1 and T3 compared with T2, reflecting lockdown periods. Home working was not associated with psychological distress at T1 (RR = 0.92, 95% CI = 0.79 to 1.08) or T2 (RR = 0.99, 95% CI = 0.88 to 1.11), but a detrimental association was found with psychological distress at T3 (RR = 1.17, 95% CI = 1.05 to 1.30). Study limitations include the fact that pre-pandemic home working propensities were derived from external sources, no information was collected on home working dosage and possible reverse association between change in wellbeing and home working likelihood. Conclusions No clear evidence of an association between home working and mental wellbeing was found, apart from greater risk of psychological distress during the second lockdown, but differences across subgroups (e.g., by sex or level of education) may exist. Longer term shifts to home working might not have adverse impacts on population wellbeing in the absence of pandemic restrictions but further monitoring of health inequalities is required.
Implementing Smoking Cessation Interventions for Tobacco Users Within Oncology Settings
Authors: Alison L. Young, Elena Stefanovska, Christine Paul, Kristen McCarter, Melissa McEnallay, Jordan Tait, Shalini Vinod, Kate White, Fiona Day, Emily Stone
Journal: JAMA Oncology (2023)

Patients with cancer who continue to smoke tobacco experience greater treatment-related complications, higher risk of secondary cancers, and greater mortality. Despite research to improve smoking cessation care within clinical oncology, implementation of proposed interventions within routine care remains challenging.